Results of Our First Nine Intraportal Islet Allografts in Type 1, Insulin-Dependent Diabetic Patients

Dw, Scharp; Pe, Lacy; Jv, Santiago; Cs, McCullough; Lg, Weide; Pj, Boyle; Falqui, Luca; Marchetti, Piero; Ricordi, Camillo; Rl, Gingerich

doi:10.1097/00007890-199101000-00012

Cited by 193 publications

(71 citation statements)

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“…This study could have important clinical relevance, because clinical islet transplantation has been successful in IDDM patients (3,4). Although CFA therapy would not be applicable clinically, BCG vaccine could be used as an immunomodulating agent in humans.…”

Section: Discussionmentioning

confidence: 99%

“…The NOD mouse is an excellent animal model of human IDDM (2). Recently, pancreatic islet cell transplantation has induced long-term, insulin independence in IDDM patients (3,4). In addition to recognition of transplanted islets as an allograft, a confounding problem facing all islet-transplanted IDDM patients is autoimmune destruction of the islet graft by the disease process (autoimmunity), resulting in recurrent IDDM.…”

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confidence: 99%

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Prevention of Recurrence of IDDM in Islet-Transplanted Diabetic NOD Mice by Adjuvant Immunotherapy

et al. 1992

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Insulin-dependent diabetes mellitus (IDDM) involves the destruction of the insulin-producing cells in the islets of Langerhans. One possible cure is by transplanting the islet cells; however, transplanted islets, even between identical twins, are subject to autoimmune destruction by the disease process, resulting in diabetes recurrence. We recently reported that complete Freund's adjuvant (CFA), an immunomodulating agent, prevented development of autoimmune diabetes in the NOD mouse. In this study, we evaluated adjuvant therapy in prevention of autoimmune destruction and rejection of transplanted islets in diabetic NOD mice. After transplantation, untreated syngeneic islet recipients (n = 16) initially became normoglycemic and then hyperglycemic, with a median survival time (MST) of the graft of 17 days. When CFA was administered at the time of transplantation, 11 of 13 CFA-treated syngeneic islet recipients remained normoglycemic long term (>100 days) with an MST >107 days. Ten of 11 mice maintained indefinite normoglycemia until the conclusion of follow-up (101 to 172 days). When adjuvant therapy was used in conjunction with allogeneic islet transplantation, graft survival was not extended, with MST being similar to the untreated allogeneic islet recipients (12 [n = 5] and 13 [n = 5] days, respectively). The extended acceptance of second syngeneic islet grafts by CFA-treated mice indicates that the persistent autoimmunity against the transplanted islets can be reversed in the diabetic NOD mice after CFA treatment.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Prevention of Recurrence of IDDM in Islet-Transplanted Diabetic NOD Mice by Adjuvant Immunotherapy

et al. 1992

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“…The observation may be of some importance, since most studies show that islet tissue from more than one donor is needed to reverse the diabetic state of the recipients in clinical TR, despite a recent report showing successful clinical islet allotransplantation with islets procured from a single donor. [8][9][10] Although FK506 prolonged islet allograft survival from single-and two-donor strains transplanted under KC, the result achieved in the former group was significantly better. One possible explanation is the higher immunogenicity of the mixed-islet preparation.…”

Section: Discussionmentioning

confidence: 99%

Successful islet allotransplantation in diabetic rats immunosuppressed with FK506: A functional and immunological study

et al. 1994

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The effect of a novel immunosuppressive agent, FK506, on fresh islet allografts was evaluated in diabetic rats across major histocompatibility complex (MHC) barriers with respect to the transplantation (TR) site, islet source, treatment regimen, and antidonor antibody (Ab) titers of the recipients after TR. The functional periods of Wistar (Wi) islets transplanted under kidney capsule (KC) or intraportally (IPo) and of a mixture of Wi and Lewis (Le) islets under KC or IPo in nonimmunosuppressed ACI rat recipients were 6.9 ± 0.4 (n = 7), 6.4 ± 0.5 (n = 7), 5.6 ± 0.4 (n = 7), and 6.2 ± 0.4 (n = 5) days, respectively. FK506 treatment at 1 mg/kg/d intramuscularly (IM) for 2 weeks (protocol I) following islet TR under KC and IPo significantly prolonged the allograft function to more than 71.8 ± 11.3 (n = 10) and 161.7 ± 18.6 (n = 11) days, respectively. Additional treatment with FK506 at 1 mg/kg/wk (protocol II) further increased the islet survival under KC to more than 212.6 ± 22.3 (n = 8) days. With this FK506 treatment protocol, the Wi + Le mixed-islet allograft function was extended to more than 106.1 ± 10.5 (n = 7) and 167.9 ± 28.6 (n = 7) days under KC and IPo, respectively. Nephrectomy in 8/8 ACI rats with long-term-functioning Wi (n = 6) and Wi + Le (n = 2) islet allografts resulted in their return to hyperglycemia. Immunohistochemical staining showed abundant insulin-positive cells at the graft site, with small numbers of CD4-and CD8-positive cells present in the vicinity of the normal-appearing islets. Macrophages were not detected. The immunosuppressive effect of FK506 was further tested In ACI rats presensitized by a previous Wi islet TR. When the duration between the first and second TR under KC was 114.3 ± 20.5 days, protocol II treatment significantly prolonged the graft function to more than 152.9 ± 28.7 (n = 8) days. However, with a short duration of about 2 weeks between the two TRs, the same FK506 protocol achieved islet graft function of 14.0 ± 3.8 days (n = 7). Additional immunosuppression with cyclophosphamide did not further improve the survival time. Antidonor Abs detected in ACI recipients of Wi islet allografts were significantly lower in the FK506-treated animals compared with the nontreatmant group. Wi and Le skin grafts performed in three ACI rats with long-term-functioning Wi islets IPo caused the rejection of the islet allografts. Skin grafts were also rejected in the first-set fashion. Six ACI recipients with longterm-functioning IPo Wi islet allografts were rendered hyperglycemic by streptozocin (STZ) injection. Long-term normoglycemia without further FK506 immunosuppression was achieved following retransplantation with fresh Wi islets IPo (n = 2), but not under KC (n = 2). The results of the present study indicate that FK506 was an effective immunosuppressant for islet allotransplantation in diabetic ACI rats across MHC barriers with islets from two donor strains, as well as in sensitized recipients whose antidonor activities had subsided. The efficacy of the immunosuppressio...

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“…The alternative appealing approach of transplanting the isolated islets of Langerhans only was attempted during the 1970s but did not result in success (defined as insulin independence) until 1990 in a patient with postpancreatectomy diabetes [106] and 1991 in a patient with type I diabetes [107]. Success with this procedure still is achieved only in occasional cases.…”

Section: Quarter Century After 1974mentioning

confidence: 99%

Historic Landmarks in Clinical Transplantation: Conclusions from the Consensus Conference at the University of California, Los Angeles

Groth

Brent²,

Calne

et al. 2000

World j. surg.

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The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contributions of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here in six tables and annotated with references.The symposium making up this issue of the Journal was held at the University of California, Los Angeles (UCLA) and announced by the Department of Surgery hosts as "a unique and historic meeting at which pioneers of transplantation from around the world will present and discuss landmarks in the advancement of transplantation biology." The participants (in alphabetical order) were: Leslie B. Brent (London), Roy Y. Calne (Cambridge, UK), Jean Dausset (Paris), Robert A. Good (St. Petersburg, FL), Joseph E. Murray (Boston), Norman E.Correspondence to: Carl G. Groth. NIH Public Access Author ManuscriptWorld J Surg. Author manuscript; available in PMC 2010 November 1. Published in final edited form as:World J Surg. 2000 July ; 24(7): 834-843. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptShumway (Palo Alto), Robert S. Schwartz (Boston), Thomas E. Starzl (Pittsburgh), Paul I. Terasaki (Los Angeles), E. Donnall Thomas (Seattle), Jon J. van Rood (Leiden).Each of these 11 pioneers provided for publication their reflections about their own unique contributions. The ultimate objective, however, was to reach a consensus by the group on what were the most critical historical discoveries that made transplantation a form of clinical therapy. Carl G. Groth (Stockholm) was invited to be the Chairman for these consensus deliberations and to prepare the executive summary.Historical landmark status was restricted to contributions made at least a quarter of a century ago. By this time it had been established that rejection of organ allografts could be prevented or reversed with immunosuppressive drugs and that variable donor-specific immunologic tolerance of the graft subsequently developed in many patients. Long-term survival of human recipients of organ and bone marrow allografts had been repeatedly obtained, ensuring continuation of such clinical efforts. A large number of HLA antigens had been discovered, allowing efforts at tissue matching to proceed. The scientific articles annotating this progress are listed in six tables under the following headings: transplantation immunology, bone marrow transplantation, renal transplantation, liver transplantation, heart transplantation, and tissue matching. The material presented in these tables, including the citations, originated from the participants of the symp...

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Results of Our First Nine Intraportal Islet Allografts in Type 1, Insulin-Dependent Diabetic Patients

Cited by 193 publications

References 0 publications

Prevention of Recurrence of IDDM in Islet-Transplanted Diabetic NOD Mice by Adjuvant Immunotherapy

Prevention of Recurrence of IDDM in Islet-Transplanted Diabetic NOD Mice by Adjuvant Immunotherapy

Successful islet allotransplantation in diabetic rats immunosuppressed with FK506: A functional and immunological study

Historic Landmarks in Clinical Transplantation: Conclusions from the Consensus Conference at the University of California, Los Angeles

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